The present invention is directed to novel fused aryl and heteroaryl bridged indenopyrrolocarbazoles, which are referred to herein as xe2x80x9cbridged indenopyrrolocarbazoles.xe2x80x9d The invention also is directed to methods for making and using the bridged indenopyrrolocarbazoles.
The microbial-derived material referred to as xe2x80x9cK-252axe2x80x9d is a unique compound which has gained significant attention over the past several years due to the variety of functional activities which it possesses. K-252a is an indolocarbazole alkaloid that was originally isolated from a Nocardiosis sp. culture (Kase, H et al. 39 J. Antibiotics 1059, 1986). K-252a is an inhibitor of several enzymes, including protein kinase C (PKC) which plays a central role in regulating cell functions, and trk tyrosine kinase. The reported functional activities of K-252a and its derivatives are numerous and diverse: tumor inhibition (See U.S. Pat. Nos. 4,877,776, 4,923,986, and 5,063,330; European Publication 238,011 in the name of Nomato); anti-insecticidal activity (See U.S. Pat. No. 4,735,939); inhibition of inflammation (See U.S. Pat. No. 4,816,450); treatment of diseases associated with neuronal cells (See U.S. Pat. Nos. 5,461,146; 5,621,100; 5,621,101; and WIPO Publication WO 94/02488, published Feb. 3, 1994 in the names of Cephalon, Inc. and Kyowa Hakko Kogyo Co., Ltd.); and treatment of prostate disease (See U.S. Pat. Nos. 5,516,771; and 5,654,427). K-252a also has been reported to inhibit IL-2 production (See Grove, D. S. et al., Experimental Cell Research 193: 175-182, 1991).
The reported indolocarbazoles share several common attributes. In particular, each comprises three five member rings which all include a nitrogen moiety; staurosporine (derived from Streptomyces sp.) and K-252a each further comprise a sugar moiety linked via two N-glycosidic bonds. Both K-252a and staurosporine have been extensively studied with respect to their utility as therapeutic agents. The indolocarbazoles are generally lypophilic which allows for their comparative ease in crossing biological membranes, and, unlike proteinaceous materials, they manifest a longer in vivo half life.
Although K-252a is normally derived from culture media via a fermentation process, the total synthesis of the natural (+) isomer and the unnatural (xe2x88x92) isomer, in which the three chiral carbons of the sugar have the opposite configurations, has been achieved (See Wood et al., J. Am. Chem. Soc. 117: 10413, 1995, and WIPO Publication WO 97/07081). However, this synthesis is not practical for commercial use.
In addition to the indolocarbazole alkaloids represented by K-252a and staurosporine, synthetic small organic molecules which are biologically active and known as fused pyrrolocarbazoles have been prepared (See U.S. Pat. Nos. 5,475,110; 5,591,855; 5,594,009; 5,705,511; and 5,616,724).
Fused isoindolones which are non-indole-containing molecules that can be chemically synthesized de novo are also known (See WIPO Publication WO 97/21677).
Certain bis-indolylmaleimide macrocyclic derivatives have also been reported (See for example U.S. Pat. Nos. 5,710,145; 5,672,618; 5,552,396; and 5,545,636).
Sugar derivatives of indolopyrrolocarbazoles also have been reported (see WIPO Publication WO98/07433).
There remains a need for novel pyrrolocarbazole derivatives that possess beneficial properties. This invention is directed to this, as well as other, important ends.
The present invention is directed to novel fused aryl and heteroaryl bridged indenopyrrolocarbazoles, which are referred to herein as xe2x80x9cbridged indenopyrrolocarbazoles.xe2x80x9d Exemplary compounds of the invention have the general Formula I: 
Constituent members and preferred embodiments are disclosed in detail infra. The compounds are useful, inter alia, for enhancing trophic factor-induced activities of trophic factor responsive cells, e.g., cholinergic neurons, and may also function as survival-promoting agents for other neuronal cell types, e.g., dopaminergic and glutamatergic, and are thus beneficial pharmacological and therapeutic agents. The present compounds are also useful in the treatment of disorders associated with decreased ChAT activity or the death or injury to spinal cord motoneurons, and also have utility in diseases associated with apoptotic cell death of the central and peripheral nervous system, immune system, and in inflammatory diseases.
The certain bridged indenopyrrolocarbazole compounds described herein may also find utility in the treatment of disease states involving malignant cell proliferation, such as cancer.
Compositions containing the subject compounds, and methods for using the subject compounds, are disclosed. Methodologies for making the present bridged indenopyrrolocarbazoles are also disclosed. Other useful methodologies will be apparent to those skilled in the art, once armed with the present disclosure. These and other features of the compounds of the subject invention are set forth in more detail below.